Cell proliferation is the increase in cell numbers as a result of cell growth and division. Generally, cells do not proliferate unless they receive signals that instruct them to do so. In the latter case, complex signal transduction networks are initiated within the cell.
The phosphoinositide 3-kinase pathway is one of the key pathways activated during cell proliferation. Phosphoinositide 3-kinase (PI3-kinase or PI3K) phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) on the 3′OH position to produce phopsphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3 or PIP3). The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) dephosphoryates PIP3 to PIP2, thereby terminating PI3K-dependent signaling. PIP3 propagates intracellular signaling leading to the proliferation of the cell.
In particular, the PI3K pathway is implicated in a variety of physiological and pathological functions operative in various human diseases such as cancer, metabolic, inflammatory and cardiovascular diseases (Wymann M P, Nat Rev Mol Cell Biol. 2008 February; 9(2):162-76., Wymann M P, Curr Opin Cell Biol. 2005 April; 17(2):141-9).
Of the three classes of PI3Ks grouped according to structure and function, Class IA PI3K is the one most implicated in human cancer. It consists of three isoforms, named PI3Kalpha, -beta and -delta, wherein the role of PI3Kalpha as a central signaling molecule downstream of receptor tyrosine kinases (RTKs) and its involvement, in tumorigenesis, growth control and cellular survival has been demonstrated. In fact, activation of the signaling pathway by mutation or amplification of PI3Kalpha or mutation/deletion of the phosphatase PTEN (the most important negative regulator of the pathway) has been found in a large proportion of cancers of different origin. (I. Vivanco & C. L. Sawyers, Nature Reviews 2002, 2:489-501).
Inhibition of PI3K signaling can diminish cell proliferation, and in some circumstances, promote cell death. As a consequence, components of this pathway present attractive targets for cancer therapeutics and likewise inhibitors targeting this pathway are interesting candidates for the treatment of cancer.
Examples of PI3K inhibitors are disclosed in WO 2006/044823, WO 2006/040279 and WO 2009/112565. Nevertheless, there is a need to provide compounds acting as inhibitors of the PI3K pathway.
Thus, the technical problem underlying the present invention is to provide inhibitors useful in the prevention and/or treatment of diseases characterized by excessive or abnormal cell proliferation, such as cancer.